3-unsubstituted steroids of the pregnane series



United States Patent 3,053,862 3-UNSUBSTITUTED STEROIDS OF THE PREGNANE SERIES Albert Bowers and James C. Orr, Mexico City, Mexico,

assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Aug. 22, 1961, Ser. No. 133,069 30 Claims. (Cl. 260397.4)

i---ORI R i O HAL In the above formulas R represents hydrogen or methyl; R represents hydrogen or a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms and R represents formyl (--CHO) or CH --OR wherein R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms. In the saturated compounds R may be in the 2oz or 25 position.

The acyl groups are derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substi-tuted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropiona-te, aminoacetate and B-chloropropionate.

The novel compounds represented by the above formulas are potent progestational agents. They also exhibit anti-estrogenic, antigonadotrophic and anti-androgenic activities. They are useful in the treatment of premenstrual tension and lower chloesterol level in blood serum and adrenal gland. In addition they are diuretic and anti-a1dosterone agents.

The novel compounds of the present invention which contain the formyl or hydroxymethyl group at C-2 and unsaturation in ring A are prepared by a process illustrated by the following equation:

O-GHz O-GH:

Cit)

CHaOH In the above formulas R has the same meaning as above set forth and Ac represents the acyl radical derived from a hydrocarbon carboxylic acid of the type mentioned previously and is preferably acetyl.

In practicing the process outlined above the starting compound or the 19-nor derivative (I) is prepared by treating Reichsteins compound S or the l9-nor derivative with formaldehyde in the presence of an acid, preferably hydrochloric acid to give the corresponding l7,20;2 0,2 lbismethylenedioxy-A -pregnen-3-one derivative which upon hydrogenation with, for example, lithium in liquid ammonia affords the corresponding 17,20;20,21-bismethylenedioxy-A -pregnen-3-one derivative which upon hydrogenation with, for example, lithium in liquid ammonia affords the corresponding l7,20;20,21-bismethylenedioxy allopregnan 3 one derivative (I). This compound is treated with ethyl formate in the presence of an alkali metal hydride such as sodium hydride and in a solvent inert to both of these reagents such as benzene. The sodium salt thus obtained is hydrolyzed with an acid, preferably aqueous hydrochloric acid, afiording the respective 2-hydroxyrnethylene-l7,20;20,21-bismethylenedioxy-allopregnan-3-one derivative (II). The 2-hydroxymethylene group is methylated with a suitable reagent, such as diazomethane, thus giving the corresponding Z-methoxymethylene-17,20;20,2l-bismethylenedioxy-allopregnan-B-one derivative which upon reduction of the 3-keto group, preferably with sodium borohydride, and hydrolysis of the resulting Sfi-hydroxy compound in a very mild acid medium yields the corresponding 2-formyl-17,20;20,21-bismethylenedioxy-A -allopregnene derivative (III).

Upon reduction of the formyl group of the latter compound with a double metal hydride, such as sodium borohydride, there is afforded the respective Z-hydroxymethyl- 17,20;20,2l-bismethylenedioxy A allopregnene derivatire which upon conventional acetylation yields the corresponding Z-acetoxymethyl derivative. Upon treatment of the latter compound with an acid such as 80% acetic acid, at approximately 100 C. for a period of time of the order of 7 hours, there is removed the protective bismethylenedioxy moiety to regenerate the dihydroxyacetone side chain at C-17 and thus form a 2-acetoxymethyl- A -allopregnene-17u,21-diol-20-one derivative (IV). To form the 21-desoxy derivative, the latter compound is treated with tosyl chloride in a solvent such as pyridine to form the Zl-tosylate which upon subsequent reaction with sodium iodide in a suitable medium such as acetic acid results in the formation of the corresponding 2-acetoxymethyl-A -allopregnen-l7ot-ol-20one. Upon conventional saponification, the latter compound is converted into methyl-l7,20;20,2l-bismethylenedioxy A -pregnadiene derivative which upon conventional acetylation in pyridine furnishes the respective Z-acetoxymethyl derivative (VIII).

Removal of the bismethylenedioxy grouping from the 2-formyl-17,20;20,2l-bismethylenedioxy A pregnadiene (VII) and from the 2-acetoxymethyl-17,20;20,21-bismethylenedioxy-A -pregnadiene (VIII) in the manner described previously, aifords the corresponding 2-fo1myl and 2-acetoxymethyl A pregnadiene-l7u,2ldiol-20 one derivatives. Upon further treatment of these latter compounds with tosyl chloride, followed by reaction with sodium iodide and acetic acid, there is finally afforded the corresponding 21-desoxy compounds, 2-forrnyl-A -pregnadien-l7a-ol-20-one (X), 2-acetoxymethyl A pregl5 the 2-hydroxymethyl-A -allopregnen-l7a-ol-20-one derivanadien-17a-ol-20-one and the 19-nor derivatives thereof. tive (V). Upon conventional saponification, the latter Z-acetoxy- Following a second reaction sequence, the 2-formyl-l7, methyl compounds are converted into the corresponding ;20,21 bismethylenedioxy-A -allopregnene compound 2 hydroxymethyl A pregnadien l7a-ol-20-one de- (III) or the l9-nor derivative is treated with a large ex- 20 rivatives (IX). cess of a hydrocarbon carboxylic acid anhydride such as In a similar manner, 2-formyl-A -allopregnene-17a-olacetic anhydride and a large excess of the corresponding 20-one (XI) and the 19-nor derivative are produced from acyl chloride such as acetyl chloride, atfording the corthe corresponding 2-formyl-M-allopregnene-l7a,2l-dio1- responding 2-acyloxymethylene-17,20;20,2l-bismethylene- 20-one obtained by removal of the bismethylenedioxy dioxy-A -allopregnene compound (VI). Upon treatment moiety from the respective 2-formyl-17,20;20,21-bisof this compound with N-bromsuccinimide in a suitable methylenedioxy-allopregnene derivative (III). solvent such as dioxane in the presence of a mild acid, The novel Z-methyl compounds of the present invenpreferably perchloric acid, there is formed the correspondtion are prepared by the process illustrated by the following 2-formyl-4I3-bromo 17,20;20,21 bismethylenedioxying equation. A -allopregnene compound which upon dehydrobromina- In the following formulas R has the same meaning as tion with, for example, calcium carbonate and dimethylheretofore set forth. formamide affords the respective 2-formyl-17,20;20,21-bis- In Practicing the above Outlined P cess, the above de- /o0H, 0-0111 H20\ l H2C O-C-O\ O-GO CH2 \OH; 0/ H R i R OHa- II XII 0- 2 O-GH: H20\ i H2O L /CH2 /OH2 o o CH3 CH3" I HO" 1 XIV XIII methylenedioxy-A -pregnadiene derivative (VII). Upon reduction of this compound, preferably with sodium boro- OHrOH CH;

scribed Z-hydroxymethylene 17,20;20,2l-bismethylenedioxy-allopregnan-3-one or the 19-nor derivative (II) is hydride, there is afforded the corresponding Z-hydroxy- 7 hydrogenated in the presence of a catalyst, such as 10% 0 5 E, R IQ 1 :0 is n R Ha I Ito-ib- XVIII XXII acid such as 80% acetic acid the 17,20;20,2l-bisrnethylenedioxy group is hydrolyzed to give the corresponding 2- methyl-M-allopregnene-l7a,21 diol 2O one derivative (XV). Treatment of this compound with tosyl chloride in pyridine and subsequent reaction of the 21-tosy1ate obtained with sodium iodide in a suitable solvent such as acetic acid, furnishes the respective 2-methy1-A -allopregnene-17a-ol-20-one (XVI) The preparation of the novel saturated compounds of 10 the present invention which contain the formyl or hydroxymethyl group at C-2 are illustrated by the following equation:

CH3 CH =o T o 3 v H O-CE In the above formulas R, R R and Ac have the same meaning as previously described.

In practicing the process above outlined, the hereinbefore obtained 2-forrnyl-17,20;20,2l-bismethylenedioxy- A -allopregnene or the l9-nor derivative thereof (III) is treated with an alkali metal such as lithium in liquid ammonia affording the corresponding 2a-formyl-17,20;20, 2l-bismethylenedioxy-allopregnane derivative (XIX). Reduction of this compound and conventional acetylation of the 2a-hydroxymethyl derivative obtained, yields the corresponding 2oc-acetoxy-methyl-17,20;20,2l-bismethylenedioxy-allopregnane derivative (XXI). The above obtained 2tx-forrnyl and Za-acetQXymethyL17,2O;20,21-bismethylenedioxyallopregnane derivatives (XIX) and (XXI) upon hydrolysis of the 17,20;20,2l-bismethylenedioxy group and subsequent treatment with tosyl chloride and sodium iodide in order to eliminate the 21-hydroxyl group of the intermediate compounds thus formed, there is afforded correspondingly the 2rx-formyl-allopregnane-17a-ol-20-one compound (XX) and the respective 2 x-acetoxymethyl-allopregnane-l7u-ol-20-one derivative. The latter compound on conventional saponification of the acetoxy group affords the corresponding 2a-hydroxymethyl derivative (XXII).

The hereinabove obtained 2-formyl-A -allopregnene- 17cc-Ol-20-OI16 derivative (XI) on hydrogenation in the presence of a suitable catalyst such as platinum oxide in a solvent, preferably ethyl acetate, gives the corresponding 2,8 formyl allopregnan l7a-Ol-20-One compound (XVIII).

The heretofore obtained 2, 25, and 2a-formyl derivatives are oxidized to the corresponding 2, 2B and 2ot-carboxy compounds by treatment with a suitable agent, as for example chromium trioxide in pyridine.

The hereinabove described 2-hydroxymethyl-A -allopregnene compounds (V) or their 2-acyloxymethyl derivatives are converted into the corresponding ZB-hydroxymethyl-allopregnane compound or the 2B-acyloxyrnethyl derivative (XVII) by hydrogenation in the presence of a catalyst, preferably platinum oxide and in an organic solvent such as ethylacetate.

The hydroxymethyl derivatives of the present invention are conventionally acylated in pyridine with an acylating agent, as for example an anhydride of a hydrocarbon carboxylic acid of the type described hereinabove, to give the corresponding acyloxymethyl derivatives.

The above obtained compounds with a l7a-hydroxy1 group are conventionally acylated with an excess of acylating agent in the presence of a p-toluenesulfonic acid thus furnishing the corresponding 17a-acyloxy compound. When there is also present in the molecule a formyl group, subsequent treatment of the 17a-acyloxy compound in a mild basic medium such as a dilute potassium hydroxide solution, prevents the presence of an enol ester of the formyl in the final compound.

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

Example I A solution of g. of Reichsteins compound S, in 40 cc. of 37% aqueous formaldehyde was treated with 0.5 cc. of concentrated hydrochloric acid and the mixture stirred for 48 hours at room temperature. It was then poured into water, the formed precipitate filtered ofi, washed with water to neutral and dried under vacuum thus afiording 17,20;20,2.1 hismethylenedioxy A -pregnen-3- one.

When applying the same method to the l9-nor Reichsteins compound S (Djerassi et al., US. Patent 2,753- 342) there was obtained 17,20;20,2l-bismethylenedioxy- 19-nor A -pregnen-3-one.

Example II A solution of 4 g. of l7,2();21-bismethylenedioxy-A pregnen-B-one in cc. of dioxane-ether (1:1) was added in a steady stream to a solution of 0.4 g. of lithium in 400 cc. of anhydrous liquid ammonia with good stirring. At the end of the addition the blue color was discharged by the addition of 20 g. of ammonium chloride and the ammonia was allowed to evaporate. The product was extracted with ether, 'washed with water, dried and the ether evaporated to aiford a gum which was adsorbed from cc. of benzene onto g. of alumina. Elution with benzene ether afforded a product which upon recrystallization from acetone-hexane gave l7,20;20,2lbismethylenedioxy-allopregnan-3-one with a melting point of 234236, [u] 67.

Treatment of 17,2O;2O,2l-bismethylenedioxy-l9-nor-A pregnen-3-one by the same procedure afforded 17,20;20, 2l-bismethylenedioxy-19-nor-allopregnan-3-one.

Example 111 To a solution of 3 g. of 17,20;20,21-bisrnethylenedioxyallopregnan-3-one in 60 cc. of anhydrous benzene was added 3 cc. of ethyl formate and 1.3 g. of sodium hydride, suspended in mineral oil While cooling and stirring under an atmosphere of nitrogen. The mixture was stirred for 24 hours at room temperature, hexane was added until complete precipitation, the solid was collected and dried under vacuum. The crude material was suspended in aqueous hydrochloric acid and was stirred at room temperature for half hour. The precipitate was collected, Washed with water and dried. Recrystallization from methylene chloride-hexane gave 2-hydroxymethylene-l7, 20;20,21-bismethylenedioxy-allopregnan-3-one, M.P. 228 229, [ab-48, 7\ max. 282-4 m r; log e 3.97.

Following the same procedure there was treated 17,20; 20,21-bismethylenedi0xy-19-nor-allopregnan 3 one, furnishing Z-hydroxymethylene-17,20; 20,2l-hismethylenedioxy-19-nor-allopregnan-3-one.

Example IV To a solution of 3 g. of 2-hydroxymethylene-17,20;

20,21-bismethylenedioxy-allopregnan-3-one in 60 cc. of

Example V A solution of 2 g. of sodium borohydride in 30cc. of methanol was added with stirring to a solution of 2 g. of 2 methoxymethylene 17,20;20,21-bismethylenedioxyallopregnan-3-one in 40 cc. of tetrahydrofuran. The mixture was kept at room temperature overnight, the excess reagent was decomposed by addition of acetic acid, the resulting solution concentrated to small volume in vacno and diluted with water. The product was extracted with ethyl acetate, the extract washed with water, dried and evaporated. Crystallization of the s lid from acetone-hexane gave 2-methoxymethylene-17,20;20, 21-bis1nethylenedioxy-allopregnan-3,B-ol.

Upon treatment by the same procedure of Z-methoxymethylene 17,20;20,21 bismethylenedioxy-l9-nor-allopregnan-3-one there was obtained Z-methoxymethylene- 17,20;20,21 bismethylenedioxy 19 nor allopregnan- 35-01.

Example VI 1.5 g. of Z-methoxymethylene-l7,20;20,2l-bismethylenedioxy-allopregnan-Bfl-ol in 30 cc. of warm methanol were treated with 0.02 cc. of concentrated hydrochloric acid and the resulting mixture was allowed to stand for 3 minutes. Then it was poured into a large excess of water, the formed precipitate filtered ofi, washed and recrystallized from acetone thus afiording 2-formyl-17,20; 20,21-bismethylenedioxy-A -allopregnene, M.P. 240-2"; [ab-16; A max. 232 m log 6 4.14. When applying this method to 2-methoxymethylene- 17,20;20,21 bismethylenedioxy-l9-nor-allopregnan-3p-ol, there was obtained Z-formyl 17,20;20,21-bismethylenedioxy-19-norn -allopregnene.

Example VII 1 g. of 2-forrnyl-17,20;20,2l-bismethylenedioxy-M- allopregnene was heated on a steam bath with 100 cc. of 80% acetic acid under nitrogen for 7 hours, it was then concentrated under vacuum to a small volume and poured into water. The precipitate was collected, washed well with water, dried and recrystallized from acetonehexane, thus furnishing 2-formyl-A allopregnene-17a, 21-diol-20-one, M.P. 2379, [ab-F94", A max. 232, log 6 4.14.

By the same technique was treated 2-formyl-17,20; 20,2l-bismethylenedioxy-19-nor-A -al1opregnene thus furnishing 2 formyl-19-nor-A -a1lopregnene-17:1,21-di0l-20- one.

Example VIII A solution of 1.5 g. of 2-formyl-A -allopregnene-17e, 21-diol-20-one in 15 cc. of pyridine was cooled to C. Under stirring there was added 0.5 g. of tosyl chloride, the mixture was kept for 16 hours at 0 C., diluted with 100 cc. of chloroform, washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and again with water, dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. Thus there was obtained the crude Z-formyl- A -allopregnene-17a,21-diol-20-one-21-tosy1ate.

A solution of 1 g. of the above crude compound in 50 cc. of glacial acetic acid was treated with 3 g. of sodium iodide and the mixture was refluxed for 2 hours, poured into ice water and extracted several times with methylene chloride; the extracts were combined, washed successively with aqueous sodium carbonate solution, sodium sulfite solution and water and then evaporated. By crystallization of the residue from acetone-hexane there was obtained 2-formyl-A allopregnene 17a-ol-20-one, M.P. 224-4; [a.] +86, A max. 232 m log 6 4.12.

Upon treatment by the above technique of Z-formyl- 19-nor-A -all0pregnene-17a,21-diol-20 one, there was obtained 2-formyl-19-nor-A -allopregnene-17a-ol-20-one.

Example IX 2 formyll7,20;20,21bismethylenedioxy-A -allopregnene and 2 formyl 17,20;20,2l-bisrnethylenedioxy-l9- nor-A -allopregnene were treated following the technique described in Example V thus furnishing respectively 2- hydroxymethyl 17,20;20,21 bismethylenedioxy-A -allopregnene, and 2 -hydroxymethyl-17,20;20,21-bismethylenedioxy-l9-nor-A -allopregnene.

Example X A mixture of 1 g. of Z-hydroxymethyLl7,20,'20,2l-bismethylenedioxy-A -allopregnene, 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave 2-acetoxymethyl-17,20; 20,21 bismethylenedioxy A -allopregnene. When acetylating by this technique 2-hydroxmethyl-17,20;20,21- bismethylenedioxy-19-nor-A -allopregnene there was obtained 2 acetoxymethyl- 17,20;20,2l-bismethylenedioxy- 19-nor-A -allopregnene.

Example XI 2-acetoxymethy1-17,20; 20,2lbismethylenedioxy-A -allopregnene and 2-acetoxymethyl-17,20; 20,21-bismethy1- enedioxy-l9-r1or-A -allopregnene were treated following the technique of Example VII, thus furnishing respective- 12 1y 2-acetoxymethyl-A -allopregnene-l7a,21-diol-20 one, and 2-acetoxymethyl-19-nor-A -allopregnene-l7a,2l-diol- 20-one.

Example XII These two last named compounds were treated following exactly the procedure described in Example VIII, thus afiording correspondingly Z-acetoxymethyl-M-allopregnene-l7a-ol-20-one and 2-acetoxymethyl-l9-nor-A allopregnene-17a-ol-20-one.

Example XIII A solution of 1 g. of 2acetoxymethyl-A -allopregnenel7a-ol-20-one in 50 cc. of methanol was refluxed for 3 hours with 500 mg. of potassium hydroxide dissolved in 1 cc. of water; it was then poured into ice water, the precipitate collected, washed with water to neutral and dried, thus producing a crude compound which upon recrystallization from methylene chloride-ether afforded 2- hydroxymethyl-A -allopregnene-17a-ol-20-one.

2-acetoxymethyl-19-nor-A allopregnene-17a-ol-20-one was treated by the above technique furnishing 2-hydroxymethyl-19-nor-A -allopregnene-17a-ol-20-one.

Example XIV A solution of 5 g. of 2-formyl17,20; 20,21-bismethylenedioxy-A -allopregnene obtained according to Example VI in 50 cc. of acetic anhydride and 50 cc. of acetyl chloride was boiled for 4 hours under an atmosphere of nitrogen. The reaction mixture then was distilled almost to dryness, cooled, diluted with ether and the organic extract washed with water, then with 5% sodium bicarbonate solution and finally with water. There was thus obtained 2-acetoxymethylene-17,20; 20,21-bismethylenedioxy-M-allopregnene.

By the same technique there was treated 2-formyl- 17,20; 20,2l-bismethylenedioxy-19-nor-A allopregnene, thus furnishing 2-acetoxymethylene-17,20; 20,21-bismethylenedioxy-l9-nor-A -allopregnene.

Example K V A solution of 1 g. of 2acetoxymethylene-17,20; 20,21- bismethylenedioxy-A -allopregnene in 20 cc. of dioxane was treated with 1.5 cc. of a 0.5 N perchloric acid solution and then there were added over a period of 30 minutes 1.1 molar equivalents of N-chlorosuccinimide. The operation was conducted with constant stirring and at 5 C. The resulting mixture was further stirred for 2 hours. Water was added, the formed precipitate filtered off and dried. Crystallization from acetone-hexane afforded 2-formyl-4fl-bromo-17,20; 20,21 -bismethylenedioxy-n -allopregnene.

1 g. of the above compound was refluxed with 1 g. of calcium carbonate and 50 cc. of dimethylformamide for 30 minutes. The mixture filtered, the solvent evaporated under reduced pressure and the residue crystallized from acetone-hexane to afford 2-formyl-l7,20; 20,2l-bismethylenedioxy-n -pregnadiene. Treatment of 2-weetoxymethylene-17,20; 20,21 bismethylenedioxy l9-nor- A -pregnene aiforded 2-formyl-17,20; 20,21-bismethylenedioxy-19-nor-A -pregnadiene.

Example XVI 2-formyl-l7,20; 20,21-bismethylenedioxy-A -pregnadiene and 2-formyl-17,20; 20,2l-bismethylcnedioxy-19-norn -pregnadiene were treated following the procedure described in Example VII, thus furnishing correspondingly 2-formyl-A -pregnadiene-17a-21-diol-20-one and 2- formyl-l9-nor-A -pregnadiene-l7a-2l-diol-20-one.

Example XVII The two last named compounds were treated in accordance with Example VIH, thus affording respectively 2-formyl-A ,*-pregnadiene-17a-ol-20-one and 2-formyl-19- nor-A -pregnadiene-17a-ol-20-one.

Example XVIII 2-formyl-l7,20; 20,2l-bismethylenedioxy-A -pregnadiene and 2-formyl-l7,20; 20,2l-bismethylenedioxy-19-nor- Example XIX The two last named compounds were acetylated in accordance with Example X, thus furnishing respectively 2 acetoxymethyl 17,20; 20,21 bismethylenedioxy-A pregnadiene and 2-acetoxymethyl-17,20; 20,21-bismethylenedioxy-l9-nor-A -pregnadiene.

Example XX Treatment of these two compounds by the technique described in Example VII afforded respectively 2-acetoxymethyl-A -pregnadiene-17a,2 l-diol one and 2-acetoxymethyl-19-nor-A -pregnadiene-17a,21-diol-20-one.

Example XXI Upon treatment of the two foregoing compounds following the technique described in Example VIII, there were correspondingly obtained 2-acetoxymethyl-A -pregnadiene-l7ot-ol-20-one and Z-acetoxymethyl-19-norA pregnadiene-l7a-ol-20-one.

Example XXII Saponification of these two compounds by the method described in Example XIII, afforded respectively 2-hydroxymethylA -pregnadiene-17a-ol 20 one and 2-hydroxyrnethyl-19-nor-A 'pregnadiene-17oc-ol-20-one.

Example XXIII 7 g. of .Z-hydroXymethylene17,20; 20,21-bismethylenedioxy-allopregnan-3-one obtained in accordance with Example III were dissolved in 300 cc. of methanol and mixed with 2.5 g. of a 10% palladium on charcoal catalyst. The mixture was hydrogenated at atmospheric pressure, at approximately C. until the absorption of hydrogen ceased. The catalyst was removed by filtration, 1 g. of potassium hydroxide in 5 cc. of water was added to the solution which was then kept for one hour at room temperature. 2 cc. of acetic acid were added, the solvent was completely removed under reduced pressure, water was added to the residue and the product was extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Recrystallization from acetone-hexane afforded 2a-methyl-17,20; 20,21- bismethylenedioxy-allopregnan-3 one. Upon treatment by the same technique of 2-hydroxymethylene-17,20; 20,21-bismethylenedioxy-19-nor-allopregnan-3-one, there was obtained 2a-methyl-17,20; 20,21-bismethylenedioxy- 19-nor-allopregnan-3-one.

Example XXIV 2a-methy1-17,20; 20,21-bismethylenedioxy-allopregnan- 3-one and 2a-methyl-17,20; 20,21-bismethylenedioxy-19- nor-allopregnan-S-one were reduced following the technique of Example V, thus affording respectively 2arnethyl-17,20; 20,21-bismethylenedioxy-allopregnan-3 8-01 and 2oc-methyl-17,20; 20,2l-bismethylenedioxy-19-norallopregnan-3B-ol.

Example XXV A solution of 5 g. of 2a-methyl-17,20; 20,21-bismethylenedioxy-pregnan-3fl-ol in 25 cc. of pyridine was cooled to 0 C. Under stirring there was added 1.3 g. of tosyl chloride, the mixture was kept for 16 hours at 0 C., diluted with 100 cc. of chloroform, washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and again with water, dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. Thus there was obtained the crude 2a-methyl-17,20; 20,21 bismethylenedioxy-allopregnan- 3,8-01 tosylate. The total crude compound was refluxed with 60 cc. of 'y-collidine for 90 minutes under anhydrous conditions. The solution was cooled and filtered. The

1d filtrate was diluted with ether, washed with dilute hydrochloric acid, sodium carbonate solution and water. The dried extract was evaporated and the residue was chromatographed on neutral alumina. Crystallization of the solid fractions from acetone-hexane afforded 2-methyl- 17,20; 20,2l-bismethylenedioxy-Mellopregnene.

When applying the above techniques to 2a-methyl- 17,20; 20,2l-bismethylenedioxy-19-nor-allopregnan-3p-ol, there was obtained 2-methyl-17,20; 20,21-bismethylenedioxy-19-nor-A -al1opregnene.

Example XXVI 2-methyl-17,20; 20,21 bismethylenedioxy-A -allopregnene and 2-methyl-17,20; 20,21-bismethylenedioxy-19- nor-A -allopregnene were treated by the method delin' eated in Example VII, affording respectively 2-rnethyl-A allopregnene-17e,21-diol-20one and 2-methyl-19-nor-A allopregnene-17a,21-diol-20-one.

Example XX VII The two foregoing compounds were treated following the technique described in Example VIII, thus affording respectively 2methy1-A -a1l0pregnene-17a-ol-2Oone and Z-methyl-19-nor-A -allopregnene-l7a-ol-20-one.

Example XXVIII A solution of 5 g. of 2-formyl-17,20; 20,2l-bismethylenedioxy-A allopregnene obtained in accordance with Example VI in 12-0 cc. of dioxane-ether (1:1) was added in a steady stream to a solution of 0.5 g. of lithium in 500 cc. of anhydrous liquid ammonia with good stirring. At the end of the addition the blue color was discharged by the addition of 25 g. of ammonium chloride and the ammonia was allowed to evaporate. The product was extracted with ether, washed with water, dried and the ether evaporated to afford a gum which was absorbed from 200 cc. of benzene onto 250 g. of alumina. Elution with benzene-ether afforded a product which upon recrystallization from acetone-hexane gave 2OL-fOI'InY1-17,20; 20,21-bismethylenedioxy-allopregnane. Treatment of 2- formyl-17,20; 20,21-bismethylenedioxy 19 nor-A -allopregnene by the same procedure afforded Za-formyl- 17,20; 20,21-bismethylenedioxy-l9-nor-allopregnane.

Example XXIX 2a-fOrInYl-l7,20; 20,21bismethylenedioxy-allopregnane and 2a-formyl-l7,20; 20,2l-bismethylenedioxy-19-norallopregnane were treated following the technique described in Example VII, thus furnishing correspondingly 2a-formyl-allopregnane-17a,21-dio1-20-one and Zea-formyl-19-nor-allopregnane-17a,21-diol-20-one.

Example XXX The two foregoing compounds were treated in accordance with Example VIII, thus affording respectively 20:- formyl-allopregnane-l7a-ol-20-one, and 2oc-formyl-19-norallopregnane-17a-o1-20-one.

Example XXXI 2a-formyl-17,20; 20,21-bismethylenedioxy-allopregnane and 2a,formyl-17,20; 20,21-bismethylenedioxy-19-norallopregnane were reduced in accordance with Example V, thus correspondingly giving 2a-hydroxymethyl-17,20; 20,21-bismethylenedioxy-allopregnane and Zoc-hYdIOXY- methyl-17,20; 20,21 bismethylcnedioxy-19-nor-allopregnane.

Example XXXII Acetylation of the two foregoing compounds by the method of Example X afforded Za-acetoxymethyl-IZZO; 20,21-bismethylenedioxy-allopregnane, and 2a-acetoxymethyl 17,20; 20,2l-bismethylenedioxy-19-nor-allopregnane.

Example XXXIII These two last named compounds were treated followmg the technique of Example VII, furnishing respectively 2a-acetoxymethyl-allopregnane 17a,21 diol-20-one and 2m-acctoxymethyl-19-nor-allopregnane 170:,21 diol-20- one.

Example XXXIV Treatment of these two compounds by the procedure of Example VIII afforded 2a-acetoxymethyl-allopregnan- 17a-ol20-one and 2u-acetoxymethyl-19-nor-allopregnan- 17u-ol-20-one.

Example XXXV Saponification of these compounds by the method of Example XIII afforded Za-hydroxymethyl-allopregnan- 17wol-20-one and 2a-hydroxymethyl-l9-nor-allopregnan- 17u-ol-20-one.

Example XXXVI Example XXX VII 1 g. of 2-hydroxymethyl-A -allopregnene-l7a-ol-20-one obtained according to Example XIII was treated following the technique described in Example X, but using propionic anhydride instead of acetic anhydride thus furnishing 2-propionoxymethyl-M-allopregneue 17a-ol-20- one.

Following the same method, there were treated the starting compounds listed below giving the corresponding products hereinafter set forth:

Starting compound Product 2 hydroxymethyl 19 nor A allopregncne-17a-ol-20-one.

2 hydroxymcthyl 19 nor A preguadiened7t1-ol-20-one.

2 hydroxyrnethyl A pregna diGIIGJ'M-OI-ZO'OHB.

2a hydroxymethyl allopreg'nane 17a-ol-20-0ne.

20: hydroxymethyl 19 nor allo prcgnane-l7a-ol-20-one.

2 propionoxy-methyl 19 nor A a1lopregnene-17cx-ol-20-one.

2 propionoxymethyl-19 -nor A pregnadier1c-l7wol-20-one.

2 propionoxymethyl A preg nadiene-l7a-ol-20-one.

2a propionoxymethyl allopreg nane-l7a-ol-20-one.

2a propionoxwmethyl 19 nor allopregnane-lh-ol-Zflone.

Following exactly the same procedure but substituting propionic anhydride by caproic anhydride, cyclopentylpropionic anhydride and benzoyl chloride there were correspondingly obtained the caproxy, cyclopentylpropionoxy and benzoyloxy derivatives of the above starting com pounds.

Example XXX VIII A mixture of 1 g. of 2-formyl-A -allopregnene-17aol-20-one, 1 g. of p-toluenesulfonic acid monohydrate, 50 cc. of acetic acid and 25 cc. of acetic anhydride was kept for 24 hours at room temperature. It was then poured into water and stirred until the excess of anhydride had hydrolized. The product was isolated by methylene chloride extraction, dissolved in 20 cc. of dioxane and treated with 10 cc. of cold 2% methanolic potassium hydroxide. The mixture was kept at -5 C. for one hour and then poured into water and neutralized with dilute hydrochloric acid. Ether extraction and crystallization from acetone-hexane afforded 2-formyl-A -allopregnene- 17a'ol-20-one-17 acetate.

Following the same technique there were treated the starting compounds listed below, with the indicated anhydride atfording the corresponding products hereinafter set forth.

Starting compound Anhydride Product 2iormyl-A -allopregnene- Propionic- 17-propionate of z-formyl-n 17a-ol-20-one. allopregncnc-l7tz-ol-2O-0ue. 2-formyl-19nor-A -nllo- -do 17-propionate of 2-tormyl19- pregnene-l7a-ol-20one. ggr-A -allopregnene-17a-ol- -one. z-formyldanor-A allo- Caprolc 17-caproate of 2-forrnyl-1f pregnene-17a-ol-20-0ne. gag-A -nlloprcgncne-lhbl- 11G. Z-IOrmyl-A -pregna- Acetic IT-acetate of 2forn1yl-A diene-17aol-20-one. prcgnndicnc-l7aol-20-one. 2-I0rmy1-A pregna- Cyclopcntyl- 17-cyclopentylpropionate of (liene-17a-ol-20-0ne. propionic. z-formylh -pregnad1ene- 17a-ol-20-one. 2-formy1-19-nor-A -preg- Acetic 17-acetate of 2 lormyl-l9aiornadiene-17a-o1-20-0ne. A -prcgnadrcne-lTaolQO- one. 2-forrnyl-l9-nor-A"#preg- Caproic 17-caproate of 2-formyl-19- nndiene-lh-oLZO-onc. nor-A -prcgnadienc-17ao1-20-one. 2a-lormyl-allopregnane- Propionic.. 17-propiouate of 2a-forrnyl- 17a-ol-20-one. alloprcgnanc-l7a-0l-20-onc. 2a-formyl-allopregnane- Cyclopentyl- 17-eyclopentylpropionnte 0t 17a-0l-20-0ne. propionic. 2a-formyl-allopregnone- 17a-ol-20-one. 2a-t'ormyl-19-n0r-allo- Acetic 17-ncetate of 2a-formyl-19- pregnane-17a-ol-20-one. rzlgr-allopregnaue-l'iacl- -one. 2a formyl l9-nor-nllo- Caprotc 17-capr0ate 0t 2aI0rmyl-l9- preguane-17a-0l-20-one. gigr-allopregnaue-l'iablone.

Example XXXIX A mixture of 1 g. of 2-hydroxyrnethyl-A -allopregnene- 17a-0l-20one, l g. of p-toluenesulfonic acid monohydrate, 50 cc. of acetic acid and 25 cc. of acetic anhydride was kept for 24 hours at room temperature. It was then poured into water and stirred until the excess of anhydride had hydrolized. Isolation of the product by methylene chloride extraction and crystallization of the residue from acetone-hexane aflforded the 17-acetate of 2-acetoxymethyl-A -allopregnene-17a-ol-20-0ne.

Following the above technique there were treated the starting compounds listed below with the indicated anhydride, thus giving the corresponding products hereinafter set forth.

Starting compound Anhydridc Product;

Z-hydroxymethyl-lQ-nor Proplonlc 2-propionoxymethy1-1Q- A -nll0pregnene17a-ol nor-N-allopregnenc-lh- 20-one ol-20-one-17-propionate 2-hydroxymetl1yl-A do Z-propionoxyrnethyl-A pregnacliene-l7a-ol-20 prcgnadicnc-lh-ol-ZO- one one-17-propionato 2-hydroxymethyl-19-nor- Caproic Z-caproxymethyl-l aior- A pregnadiene-Ha- 17aol-20one-l7-caproate o1-20'0ne Za-hydroxymethyL do 2a caproxymethylallopregnanc-17a-ol-20- flllOIlIQgDBHC-lJa-Ol-ZQ- one one-17-caproate 2a-hydroxytncthyl-19- Cyclopentyl- 2a-oy0l0pentylpropionoxy nor-allopregnane-Uapropionic methyl-IQ-nor- 01-20-one allopregnane-17u-ol-20- one-l'l-cyclopcntylpropionnte Z-acetoxyznethy-N- Propionic l7-pr0pionate of 2-acetoxyallopregnenc-Ua-olmethyl A -nlloprcgnenc- 20-one Howl-20pm: 2-propionoxymethyl- Acetic IY-acetute of 2- 19-n0rA -all0pregnenepropionoxymethyl-ltlnorl7a0l-20-0I1G N-allopregnene-Ua-ol- 20-one 2-acetoxy1nethyl-A Caproic 17-eaproate of zacetoxypregnadicne 17aol-20- methyl-A preguadieneone 17a-ol20-onc 2-caproxymethyl-19-nor- Propionic- 17-propi0nate of 2 A -pregnadiene-17acaproxyineth yl-19norol-20-onc A -pregnadienedh-ol- 20-one 2a-cyc1openty1propionoxy- Acetic 17-acetato of 2amethyl-allopregnanecyclopentylpropionoxy- 17a01-20-0!1o rncthyl-nllopregnanc-Uao1-20'one 2a-propionoxymethyl- Cyelopentyl- 17-cyclopcntylpropi0nate IQ-nor-allopregnanepropionic of 2a-propionoxymethyl- 17zz-0l-ZOOI19 19n0r-al1oprcgnane-l7a- 01-20mm 2-methyl-A -all0pregnene- Acetic 17-acetate of Z-methyl-A l7a-Ol-20OI19 nllopregnene-Ucml-mno Z-mathyl-Mallopregnene- Propi0nic 17-propionate of 2-mcthyl- 17wol-20-one A -allopregnene4701-01-20- one 2methyl-19-nor-A Acetic 17-acetete of 2-mcthyl-19- allopregnene-l7a-ol-20- nor-A allopregnene-Uuone 01-20mm 2-metl1yl-19-n0r-A' Caprolc 17-caproate of 2-n1ethyl-19- allopregnene-17a-ol-20- N-allopregnene-UaoLZO- one one 17 Example XXXX Starting compound Product 2-hydroxymethyl-A -allopregnene- 2-hydroxymethyl-l9-nor-A allopregnene-17a-ol-20-one 221cctoxymethyl-A -allopregnene- 17a-ol-20-one 2-propionoxymethyl-19 nor-A al1opregnene-17a-ol20-ona 2-propionoxymethyl-lQ-nor-M- allopregnene-17a-o1-20one-17- acetate 2racetoxymethyl-A -allopregnene- Howl-20-one-17-propionate 2B-hydroxymethyl-19-norallopregnane-lM-ol-ZO-one 2fl-acetoxymethyl-allopregnane- 17a-0l-20-0ne 2B-propionoxymethyl-lQ-nor- 17a-o1-20-0ne 2fl-plropionoxymethyl-19-nora opregnane-17a-ol-20-one-17- acetate 2B-acetoxymethyl-allopregnane- 17a-ol-20-one-17-propionate wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is selected from the group consisting of formyl (CHO) and CH --OR wherein R is a member of the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

2. 2-formyl-A -allopregnene-17u-ol-20-one.

3. 2-formyl-19-nor-A -allopregnene-l7a-ol-20-one.

4. 2-hydroXymethyl-A -allopregnene-17u-ol-20-one.

5. 2 hydroxymethyl l9 nor A allopregnene 17aol-20-one.

6. 2-formy1-A -a1lopregnene-17u-ol-20-one-17-acetate.

7. 2 acetoxymethyl A allopregnene 17a o1 20- one-l7-acetate.

8. A compound of the following formula:

hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

9. 2-formyl-A -pregnadiene-17u-ol-2O-one.

10. Z-formyl-19-nor-A -pregnadiene-17u-ol-20-one.

11. 2-hydroxymethyl-A -pregnadiene-l7a-ol-20-one.

12. 2 hydroxymethyl 19-nor-A -pregnadiene-l7u-ol- 20-one.

13. 2-formyl-A -pregnadiene-17a-ol-20-one-17-acetate.

14. 2 propionoxymethyl A pregnadiene 17 a ol- 20-one-l7-propionate.

15. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is selected from the group consisting of formyl (-CHO) and CH OR wherein R is a member of the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

16. 2u-formyl-allopregnane-l7a-ol-20-one.

17. Zea-formyl-19-nor-allopregnane-l7a-o1-20-one.

18. 2a-hydroxymethyl-allopregnane-17a-o1-20-one.

19. 2a hydroxymethyl 19 nor allopregnane 17aol-20-one.

20. 2a formyl allopregnane 17a o1 20 one l7- propionate.

21. 2oz caproxymethyl allopregnane 17oz ol 20- one-17-caproate.

22. Zfl-formyl-allopregnane-l7a-ol-20-one.

23. Zfi-formyl-l9-nor-allopregnane-17a-ol-20-one.

24. 2p-hydroxymethyl-allopregnane-17a-ol-20-one.

25. Zn hydroxymethyl 19' nor allopregnane 1706- ol-20-one.

26. 2,3 acetoxymethyl allopregnane 17a ol 20'- one-17-propionate.

27. A compound of the following formula:

No references cited. 

8. A COMPOUND OF THE FOLLOWING FORMULA:
 27. A COMPOUND OF THE FOLLOWING FORMULA: 